In the description which follows, references are made to certain literature citations which are listed at the end of the specification. The contents of these are incorporated herein by reference.
One of the earliest drugs to show great promise as an anti-retroviral drug was the reverse transcriptase inhibitor, 3'-azido-3'-deoxythymidine, also known as zidovudine or AZT. AZT is a potent inhibitor of retroviral replication and has been widely used in the treatment of infection with the human immunodeficiency virus (HIV) or treatment of acquired immune deficiency syndrome (AIDS) caused by that virus.
The major limitation to the use or AZT in these therapies is its side-effect of bone marrow toxicity, resulting in granulocytopenia and anemia. This toxicity is caused mainly by a toxic metabolite of AZT, 3'-amino-3'-deoxythymidine or AMT, which is more toxic to bone marrow cells than AZT and has a longer half-life in the circulation (Cretton et al., 1991; Stagg, 1992). Depending on dosage and disease stage, up to 51% of patients treated with AZT suffer bone marrow toxicity. It would therefore be beneficial to find ways of reducing the production of AMT during AZT therapy.